The skin is susceptible to penetration by agents that sensitize the skin or irritate the skin. As used herein the term "skin-sensitizing agent" is a substance that generally causes the formation of memory cells which recognize future contact with the sensitizing agent. Such future contact can result in an adverse reaction, both locally and at remote cites on the body. In general, a "skin-irritating agent" is a substance (e.g. soap) that causes an immediate and generally localized adverse response. The response is typically in the form of redness and/or inflammation and does not extend beyond the immediate area of contact nor does it cause the formation of memory cells. As used herein, the term "adverse skin reaction preventing or treating agent" shall mean collectively agents used in the present invention against skin-sensitizing agents and/or skin-irritating agents.
Allergic reactions of the skin to skin-sensitizing agents, known as allergic contact dermatitis (ACD), are immune responses that occur in the skin. The response is the result of the penetration of the skin by a foreign substance (e.g. hapten or antigen) that provokes a skin sensitization reaction. ACD is a two phase process involving an initial induction phase followed by an elicitation phase.
The induction phase occurs immediately after first time exposure of the skin to the hapten or antigen and is characterized by the formation of immune memory cells that can subsequently recognize the specific hapten or antigen which previously entered the skin for the first time.
The elicitation phase occurs when the skin is subsequently re-exposed to the original hapten or antigen. In the elicitation phase, the skin provides an overt reaction to the presence of the hapten or antigen in the form of a skin inflammatory response.
ACD generally results in a life-time persistent memory for the specific hapten or antigen. Thus, when the skin is exposed to the hapten or antigen at a subsequent time, there is typically an immediate and often severe skin inflammatory response.
Agents that cause allergic contact dermatitis are varied and numerous and include, for example, metals (e.g. nickel, chromium, cobalt and the like) fragrances, chemicals, cosmetics, textiles, pesticides, plastics, pollen and the like (see, for example, R. J. G. Rycroft et al. "Textbook of Contact Dermatitis"). Therapeutic agents such as drugs may also cause allergic contact dermatitis particularly when administered transdermally.
Transdermal delivery of drugs provides many advantages over alternate routes of administration. Transdermal delivery systems (TDS) for delivery of drugs or other beneficial agents are wellknown (see, for example, U.S. Pat. Nos. 3,598,122, 3,598,123, 4,286,592, 4,314,557, 4,379,454, 4,599,222 and 4,573,995, which are each incorporated herein by reference). A TDS is generally composed of the following components: (a) "basic components", including backing, matrix reservoir, and an optional separate adhesive layer; (b) the drug or other therapeutic agent; (c) "additives", including solubilizers, plasticizers and permeation enhancers; and (d) "impurities" such as residual amounts of monomers, initiators, cross-linkers, etc., from the polymerization process during fabrication of the basic components.
The conditions under which TDS are administered are highly conducive to the induction of skin allergic reactions, and the following skin reactions may be expected to occur:
1. Irritant reactions to the drug, an additive, an impurity, or a combination thereof; PA1 2. Allergic reactions, especially to the low molecular weight components (drug, additive, impurity, adhesive); PA1 3. Local sweat retention syndrome resulting from prolonged skin occlusion which causes blocking of sweat ducts.
Allergic contact dermatitis presents a significant problem in the transdermal administration of therapeutic agents. It is well known that many drugs, including some currently marketed in the United States (e.g. clonidine) sensitize the skin when used in a transdermal delivery system. Skin sensitization may be produced not only by the transdermally delivered drug, but also by a non-sensitizing drug combined with skin sensitizing permeation enhancers, or a combination of a sensitizing drug and a sensitizing permeation enhancer. Penetration of these sensitizing agents into the skin and the resulting adverse reaction of the skin may persist well beyond the time that the transdermal patch is removed from the skin. The reaction of the skin may be a source of discomfort and a clinical complication in a patient suffering from such a reaction.
Unlike the response induced by skin-sensitizing agents, the non-allergic response to skin-irritating agents is immediate and localized and does not invoke activation of the immune system through the production of immune memory cells.
The most common response associated with skin-irritating agents is the onset of inflammation. The main steps of the inflammatory response include, the neurologic phase, the vascular phase and the cellular phase. In the neurologic phase transient vasoconstriction occurs typically within about 30 seconds of contact with the skin-irritating agent. Within about one to six minutes of contact, vasodilation occurs followed by the margination of neutrophils in the vessels and diapedesis, the outward passage of corpuscular elements through intact vessel walls.
The non-immune response to a skin-irritating agent is the result of a substance that causes direct toxic damage to the skin without preceding allergic sensitization. The response to contact is dependent upon the nature of the skin, the skin-irritating agent, its concentration, the situs of contact on the body and environmental factors such as humidity and temperature. Examples of potential skin-irritating agents include water, skin cleansers, industrial cleaning agents, alkalis, acids, oils, organic solvents, oxidizing agents, reducing agents, plant matter, animal matter, combinations thereof and the like.
Efforts have been made to address the problem of allergic contact dermatitis by prophylactically treating the skin to prevent the onset of the induction phase of ACD and/or to therapeutically prevent or reduce the adverse effects of the elicitation phase of ACD. For example, U.S. Pat. No. 5,202,130 discloses that lanthanide ions and organic calcium channel blockers individually can be used for the treatment of contact allergic dermatitis.
Wolfgang Diezel et al., J. Invest. Derm., Vol. 93, No. 3, pp. 322-326 (September 1989) discloses the sensitization of mice with 1-chloro-2, 4-dinitrobenzene and subsequent treatment with lanthanum citrate and diltiazem hydrochloride to prevent the onset of the induction phase of the sensitizing agent. Philip W. Ledger, et al., U.S. Pat. No. 5,120,545 disclose the prevention of skin sensitization by the administration of an antigen processing-inhibiting agent such as ammonium chloride. A method of preventing contact sensitization using steroids (e.g. corticosteroid and glucocorticoid carboxylic acid esters) is disclosed, for example, in Alfred Amkraut, U.S. Pat. No. 5,118,509 and Peter M. Ross, et al., U.S. Pat. No. 4,897,260.
A method of reducing the adverse effects of administering a sensitizing or irritating drug by using methyl nicotinate is disclosed in Michel Cormier et al., U.S. Pat. No. 5,451,407.
Methods of treating ACD through the blocking of the elicitation phase after initial exposure to a drug is disclosed, for example, in John McFadden, et al., J. Invest. Derm., Vol. 99, No. 6, pp. 784-786 (December 1992). Tuberculin-induced delayed-type hypersensitivity reaction in human skin was inhibited by topical application of verapamil hydrochloride prior to or concurrent with challenge with tuberculin.
Also, Richard L. Gallo, et al., Arch. Dermatol., Vol. 125, pp. 502-506 (April 1989) discloses the administration of the diuretic amiloride hydrochloride as a topical anti-inflammatory agent in the treatment of ACD, particularly mice sensitized with 2,4,6-trinitrobenzene.
As disclosed in commonly assigned U.S. Ser. No. 08/198,003 filed Feb. 17, 1994, and references cited therein, irradiation of skin with ultraviolet light B (UVB) is known to be immunosuppressive. These UVB effects are thought to be mediated, in part, by the UVB-induced isomerization of trans-urocanic acid (trans-UCA), a molecule which makes up about 0.5% of the total dry weight in the upper layers of human epidermis, to cis-urocanic acid (cis-UCA). Cis-UCA is known to have various immunosuppressive actions in vivo in a number of experimental systems and is believed to act through histamine-like receptors in the skin. More recently, it has been shown that the UVB impairment of the induction phase of allergic contact dermatitis to epicutaneously applied haptens in certain mouse strains depended on the participation of the cytokine, tumor necrosis factor-a (TNFa). It has been suggested that local release of TNFa may inhibit sensitization by trapping epidermal Langerhans cells and preventing them from reaching the draining lymph node where they activate T. cells.
As further disclosed in U.S. Ser. No. 08/198,003, mast cell degranulators such as cis-urocanic acid are effective for preventing or inhibiting the skin sensitizing effect of a transdermally administered therapeutic agent.
Despite these efforts and the knowledge gained regarding the cause of ACD, there remains a need to develop compositions which effectively prevent the onset of ACD or reduce the adverse affects of ACD after the person has been sensitized to an agent, as for example, a transdermally administered agent such as a drug. There is likewise the need to develop compositions which effectively prevent reactions to skin-irritating agents.
Applicants have gained the knowledge that there is a distinct process step implicated in the immune response associated with allergic contact dermatitis, which when interfered with, results in the prevention and/or treatment of ACD. This process step referred to herein as cellular signal transduction, is believed responsible for the acquisition of memory by T-lymphocytes, for the cytokine-mediated regulation of antigen presentation and for other cellular processes as well.
Applicants have also discovered that a particular class of compounds having diuretic properties, referred to herein as high ceiling or loop diuretics alone or in combination with at least one mast cell degranulator or at least one glucocorticosteroid achieves significant improvement in the desensitization of a patient's skin and prevents and/or treats inflammation of the skin. As a result, the reaction of the skin to skin-sensitizing agents or skin-irritating agents is better controlled. The present invention therefore provides prevention and/or treatment of an adverse reaction to the skin, as well as a transdermal therapy which reduces discomfort to the patient.